WO2001078711A2 - Utilisation d'inhibiteurs de phosphodiesterase specifique de gmp cyclique pour le traitement de la maladie de parkinson - Google Patents
Utilisation d'inhibiteurs de phosphodiesterase specifique de gmp cyclique pour le traitement de la maladie de parkinson Download PDFInfo
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- WO2001078711A2 WO2001078711A2 PCT/US2001/040538 US0140538W WO0178711A2 WO 2001078711 A2 WO2001078711 A2 WO 2001078711A2 US 0140538 W US0140538 W US 0140538W WO 0178711 A2 WO0178711 A2 WO 0178711A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates generally to novel therapeutic methods for treating Parkinson's Disease by administering cyclic GMP- specific phosphodiesterase inhibitor compounds.
- Parkinson's Disease is a progressive degenerative disorder of the central nervous system (CNS) characterized by tremor and impaired muscular coordination. It is fatal if untreated. PD has been reported to affect approximately one percent of Americans over fifty years of age, but unrecognized early symptoms of the disease may be present in as many as ten percent of those over 60 years of age. The current prediction is that one to one and one-half million persons in the United States may be suffering from PD. The disease may appear at any age, but the risk of developing it increases with age. The occurrence of PD is therefore expected to increase in the next one-half century as the average age of individuals in developed countries progressively increases.
- Cogwheel rigidity refers to increased tone that is felt by the examiner as a ratchet-like resistance during passive range of motion Bradykinesia means slowed nonvo tional and/or volitional movements
- the masked faces of PD are an example of slowed nonvohtional movement
- the mean duration of PD is about fourteen years However, without treatment, the period between presentation of clinical features and death is reduced to about nine years The rate of disease progression is believed to be directly correlated to the rate of neuron loss
- Symptomatic therapies are the most common form of treatment for PD These remedies attempt to fulfill the basic dictate of traditional medicine, to relieve suffering These drugs are designed to be used as either monotherapy or adjunctive symptomatic therapy but have little, if any, beneficial effects on underlying disease cause or pathogenesis
- the symptomatic compounds can be divided into two groups on the basis of their pharmacologic action - dopammergic drugs and nondopaminergic drugs Most symptomatic PD drugs attempt to replenish, mimic, or enhance the effects of brain dopamine, a neurotransmitter, because PD is thought to be due to defective dopammergic transmission in the substantia nigra of the basal ganglia Dopamine itself is neither well absorbed in the gastrointestinal tract nor effectively transported across the blood-brain barrier L-dopa is dopamine precursor therapy L-dopa crosses the blood-brain barrier penetrating into the brain, where it is converted to dopamine via the enzyme dopa decarboxylase L-dopa has poor bio
- L-dopa is formulated with a decarboxylase inhibitor.
- the decarboxylase inhibitor carbidopa is contained in virtually all L-dopa products prescribed during the last 20 years.
- L-dopa has served as the mainstay of PD therapy.
- long term treatment with L-dopa often results in disabling complications.
- Many patients develop unsustained or unpredictable responses to L-dopa along with drug-induced involuntary movements. It has even been postulated by Mena, et al., Mov Disord 7:23 (1992), that L-dopa may be neurotoxic and thereby accelerates nigral neuronal degeneration.
- dopamine agonists have been developed for use as monotherapy in early PD to postpone the need to initiate L-dopa therapy and for use as adjunctive therapy later in the disease to permit reduction of L-dopa dosing or enhancement of beneficial dopaminergic effects.
- Agonists directly stimulate dopamine receptors within the brain, and thus their action is independent of L-dopa.
- Blockade of other metabolic enzymatic pathways can also be used to enhance the effects of L-dopa or to maintain brain dopamine levels.
- One of the central metabolic pathways for dopamine is mediated via the enzyme monoamine oxidase type B (MAOB).
- MAOB monoamine oxidase type B
- Another MAOB inhibitor, lazabemide was initially tested as adjunctive therapy in PD, but it is not being actively developed at this time. Hubble, JP, Med Clinics of North America 83(2):525-536 (1999).
- the compound rasagiline also inhibits the oxidative monoamine metabolic enzymes. Rasagiline's effects in early untreated PD are being investigated. Hubble, supra.
- Cyclic nucleotide phosphodiesterases are essential regulators of cyclic nucleotide-dependent signal transduction processes. They terminate the action of the second messengers adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) by hydrolyzing them to their respective 5'- nucleoside monophosphates. Based on their biological properties, the PDEs may be classified into several general families.
- Ca 2 7calmodulin-stimulated PDE (Type I), cGMP-stimulated PDE (Type II), cGMP-inhibited PDE (Type III), cAMP-specific PDE (Type IV), cGMP-specific
- dopamine agonists with phosphodiesterase inhibitors was examined after it was discovered that the striatal dopaminergic receptor was closely associated with an adenylate cyclase.
- the actions of dopamine are mediated by an adenylate cyclase which produces cyclic AMP.
- U.S. Patent 4,147,789 discloses the combination of 6-methyl-8- thiomethyl-ergolene derivatives with nonselective phosphodiesterase inhibitors for treatment of PD.
- U.S. Patent 4,147,789 does not disclose using specific phosphodiesterase inhibitors nor does it disclose combining L-dopa with phosphodiesterase inhibitors.
- the present invention provides novel therapeutic uses for Type V PDE inhibitors in patients suffering from PD.
- the invention provides methods of preventing and/or slowing the progression of PD or reducing or eliminating clinical symptoms of PD by administering a therapeutically effective amount of one or more Type V PDE (PDE5) inhibitor(s) of the invention.
- PDE5 Type V PDE
- a "clinical symptom" of PD includes tremor, cogwheel rigidity, bradykinesia, poor postural reflexes, and any other clinically defined physical or mental manifestation of PD.
- IC 50 is defined as the concentration of a compound that results in 50% enzyme inhibition, in a single dose response experiment.
- the IC 50 value therefore is a measure of the potency of a compound to inhibit PDEs, including PDE5. Determining the IC 50 value of a compound is readily carried out by a known in vitro methodology generally described in Cheng et al., Biochem Pharmacology 22:3099-3108 (1973).
- the term “inhibiting” or “inhibits” refers to blocking the enzymatic activity of PDE5 to a sufficient degree to reduce a clinical symptom of PD or to prevent the recurrence of a clinical symptom of PD
- a pharmaceutically effective amount represents an amount of a compound that is capable of inhibiting PDE5, and causes an improvement in a clinical symptom of PD and/or prevents or reduces recurrence of the symptom
- PDE5 inhibitor refers to a compound that inhibits PDE5
- a PDE5 inhibitor useful in the present invention is a compound that inhibits PDE5 and has an IC 50 value against human recombinant PDE5 of about 10 nM or less
- the IC 50 value of the PDE5 inhibitor is about 5 nM or less, more preferably about 3 nM or less, and most preferably about 1 nM or less
- Most preferred PDE5 inhibitors are selective PDE5 inhibitors, i e , those that inhibit PDE5, but do not significantly inhibit other PDE enzymes, particularly PDE6 and PDE 1c
- a preferred PDE5 inhibitor exhibits a PDE6/PDE5 and a PDE1 c/PDE5 IC ⁇ inhibition quotient of at least 200, and can range to 1 ,000 or greater
- the PDE6/PDE5 IC 50 inhibition quotient is the ratio of the IC 50 value of a compound vs PDE6 to the IC 50
- the compound has a PDE6/PDE5 and a PDE1 c/PDE5 IC 50 inhibition quotient of at least 100 and an IC 50 for PDE5 of about 5 nM or less, e g , about 0 1 to about 5 nM Therefore, for preferred inhibitors, the IC 50 value of the PDE5 inhibitor is about 100 times less than the IC 50 value against PDE6 or PDEIc, more preferably about 500 times less than the IC 50 value against PDE6 or PDEIc, and most preferably about 1000 times less than the IC 50 value against PDE6 or PDEIc
- PDE5 inhibitors useful in the present invention vary significantly in chemical structure and the use of a PDE5 inhibitor in the present method is not dependent on a particular chemical structure
- preferred compounds having the ability to inhibit PDE5 include compounds having the structural formula (I)
- R 1 is methyl or ethyl
- R 2 is n-propyl
- R 3 is ethyl, n-propyl, or ailyl
- R 4 is
- R 13 is selected from the group consisting of hydrogen, halogen, and C h alky!;
- R 14 is selected from the group consisting of hydrogen, C ⁇ alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, halo, C 3 . 8 cycloalkyl, C 3 . 8 cycloalkylC 1 .
- aryl is phenyl or phenyl substituted with one to three substituents independently selected from the group consisting of halogen, C ⁇ alkyl, C ⁇ alkoxy, and methylenedioxy, and heteroarylC Lj alkyl, wherein heteroaryl is thienyl, furyl, or pyridyl, each optionally substituted with one to three substituents independently selected from the group consisting of halogen, C ⁇ alkyl, and C ⁇ alkoxy.
- R 15 represents an optionally substituted monocyclic aromatic ring selected from the group consisting of benzene, thiophene, furan, and pyridine, or an optionally substituted bicyclic ring
- the fused ring A is a 5- or 6-membered ring, saturated or partially or fully unsaturated, and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen;
- R 16 represents hydrogen or C ⁇ alkyl, or R 14 and R 16 together represent a 3- or 4-membered alkyl or alkenyl chain component of a 5- or 6-membered ring.
- Preferred compounds of structural formula (II) are those wherein R 13 is hydrogen, halogen, or C, 6 alkyl; R 14 is hydrogen or C h alky!; R 15 is the bicyclic ring
- Preferred compounds of structural formula (II) include:
- the compounds of structural formula (II) are particularly advantageous due to their selectivity in inhibiting PDE5 over other PDE enzymes.
- Still other exemplary PDE5 inhibitors useful in the present method are those disclosed in Daugan et al. U.S. Patent No. 6,001 ,847;
- ring C represents a 5- or 6-membered heteroaryl group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur;
- R 17 represents hydrogen or halogen
- R 19 is selected from the group consisting of hydrogen, halogen, OR h , C ⁇ alkyl, NO 2 , and NR h R'; or R 18 and R 19 are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;
- R 21 is hydrogen, or R 20 and R 21 are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom; Het represents a 5- or 6-membered heterocyc c group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and is optionally substituted with C, 4 alkyl,
- R h and R' can be the same or different, and are independently selected from hydrogen and C, 6 alkyl,
- C is a heteroaryl group containing at least one nitrogen or sulfur
- R 19 is hydrogen
- R 18 is selected from the group consisting of NR h R' and a 5- or 6-membered heterocychc group containing at least one nitrogen optionally substituted with C ⁇ alkyl
- the PDE5 inhibitors may be concurrently administered with other drugs, including other known anti-PD drugs, in which case the dosage of each agent required to exert a therapeutic effect during combinative therapy may be less than the dosage necessary for monotherapeutic effectiveness
- drugs for concurrent administration include, but are not limited to, L-dopa, carbo-levo, apomorphine, pirebedil, bromocriptine, carbergohne, pramipexole, ropinirole, selegiline, lazabemide, rasagiline, sildenafil citrate (Viagra), caffeine, Mirapex, Naprelan, Oxybutin and aspirin
- the invention further provides uses of PDE5 inhibitors in the manufacture of a medicament for treating PD
- PDE5 inhibitors possess desirable physical and biological properties, e g , a sufficient water solubility, bioavailability, and metabolic stability, for therapeutic use in the treatment of PD
- Anti-PD therapeutically effective amounts of PDE5 inhibitors include amounts effective for slowing or preventing the progression of PD and amounts effective to alleviate or reduce the clinical symptoms of PD PDE5 inhibitors can be administered to humans at doses ranging from about 0 1 mg to about 1000 mg daily or more preferably at doses ranging from about 1 mg to about 100 mg daily for adults Even more preferably, doses range from about 2mg to about 20 mg over a 24 hour period Most preferable are doses calculated to provide an effective circulating blood level Equivalent dosing of PDE5 inhibitors can be administered at longer intervals, e g , larger doses once or twice weekly The dosage of the drug may be increased or decreased, and the duration of treatment
- the specific dose may be calculated according to body weight, body surface area or organ size Further refinement of the calculations necessary to determine the appropriate dosage for treatment involving each of the above mentioned formulations is routinely made by those of ordinary skill in the art without undue experimentation Appropriate dosages may be ascertained through use of established assays for determining blood level dosages in conjunction with appropriate dose- response data The final dosage regimen will be determined by the attending physician, considering various factors which modify the action of drugs, e g , the drug ' s specific activity, the severity of the damage and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of the clinical symptoms, time of administration and other clinical factors.
- PDE5 inhibitors may be administered systemically via, e.g., oral, intravenous, intramuscular or subcutaneous routes.
- the drug may be aerosolized for pulmonary administration, formulated in a spray for nasal administration, administered intraventricularly or intrathecally into the cerebrospinal fluid, or administered intravenously via continuous infusion pump.
- the drugs may also be administered topically via, e.g., drops
- PDE5 inhibitors and another anti-PD agent can be administered simultaneously or sequentially.
- the compounds are usually administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient.
- These compositions can be administered by a variety of routes including oral, buccal, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
- compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
- the active ingredient usually is mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
- the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), oint- ments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
- the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
- compositions used in the invention can be formulated to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
- compositions preferably are formulated in a unit dosage form.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
- the active compounds generally are effective over a wide dosage range. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances.
- Example 1 describes the preparation of
- Example 2 describes an assay for PDE5 activity.
- Example 3 describes assays to measure the effects of PDE5 inhibitors.
- Example 4 describes administration of a PDE5 inhibitor compound to a patient suffering from PD.
- yeast transformation vector employed which is derived from the basic ADH2 plasmid described in V. Price et al., Methods in Enzymology, 185, pages 308-318 (1990) incorporated yeast ADH2 promoter and terminator sequences rather than ADH1 promoter and terminator sequences and the Saccharomyces cerevisiae host was the protease-deficient strain BJ2-54 deposited on August 31 , 1998 with the American Type Culture Collection, Manassas, Virginia, under accession number ATCC 74465.
- Transformed host cells were grown in 2X SC-leu medium, pH 6.2, with trace metals, and vitamins. After 24 hours, YEP medium containing glycerol was added to a final concentration of 2X YEP/3% glycerol. Approximately 24 hours later, cells were harvested, washed, and stored at -70 °C.
- Cell pellets (29 g) were thawed on ice with an equal volume of lysis buffer (25 mM Tris-CI, pH 8, 5 mM MgCI 2 , 0.25 mM dithiothreitol, 1 mM benzamidine, and 10 ⁇ M ZnSO 4 ).
- lysis buffer 25 mM Tris-CI, pH 8, 5 mM MgCI 2 , 0.25 mM dithiothreitol, 1 mM benzamidine, and 10 ⁇ M ZnSO 4 .
- Cells were lysed in a microfluidizer with N 2 at 20,000 psi. The lysate was centrifuged and filtered through 0.45 ⁇ M disposable filters. The filtrate was applied to a 150 ml column of Q Sepharose Fast Flow (Pharmacia).
- the column was washed with 1 .5 volumes of Buffer A (20 mM Bis-Tris Propane, pH 6.8, 1 mM MgCI 2 , 0.25 mM dithiothreitol, 10 ⁇ M ZnSO 4 ) and eluted with a step gradient of 125 mM NaCI in Buffer A followed by a linear gradient of 125-1000 mM NaCI in Buffer A.
- Buffer A (20 mM Bis-Tris Propane, pH 6.8, 1 mM MgCI 2 , 0.25 mM dithiothreitol, 10 ⁇ M ZnSO 4 .
- Active fractions from the linear gradient were applied to a 180 ml hydroxylapatite column in Buffer B (20 mM Bis-Tris Propane (pH 6.8), 1 mM MgCI 2 , 0.25 mM dithiothreitol, 10 ⁇ M ZnSO 4 , and 250 mM KCI). After loading, the column was washed with 2 volumes of Buffer B and eluted with a linear gradient of 0-125 mM potassium phosphate in Buffer B.
- Buffer B 20 mM Bis-Tris Propane (pH 6.8), 1 mM MgCI 2 , 0.25 mM dithiothreitol, 10 ⁇ M ZnSO 4 , and 250 mM KCI.
- Active fractions were pooled, precipitated with 60% ammonium sulfate, and resuspended in Buffer C (20 mM Bis-Tris Propane, pH 6.8, 125 mM NaCI, 0.5 mM dithiothreitol, and 10 ⁇ M ZnSO 4 ).
- Buffer C 20 mM Bis-Tris Propane, pH 6.8, 125 mM NaCI, 0.5 mM dithiothreitol, and 10 ⁇ M ZnSO 4 ).
- the pool was applied to a 140 ml column of Sephacryl S-300 HR and eluted with Buffer C. Active fractions were diluted to 50% glycerol and stored at -20 °C. The resultant preparations were about 85% pure by SDS-PAGE.
- PDE5 activity can be measured by standard assays in the art. For example, specific activity of any PDE can be determined as follows. PDE assays utilizing a charcoal separation technique are performed essentially as described in Loughney, et al., J. Biol. Chem. 277:796-806 (1996). In this assay, PDE5 activity converts [ 32 P]cGMP to
- [ 32 P]5'GMP in proportion to the amount of PDE5 activity present.
- the [ 32 P]5'GMP is then quantitatively converted to free [ 32 P] phosphate and unlabeled adenosine by the action of snake venom 5'-nucleotidase.
- the amount of [ 32 P] phosphate liberated is proportional to enzyme activity.
- the assay is performed at 30°C in a 100 ⁇ L reaction mixture containing (final concentrations) 40 mM Tris-CI (pH 8.0), 1 ⁇ M ZnSO 4 , 5 mM MgCI 2 , and 0.1 mg/ml bovine serum albumin.
- PDE5 is present in quantities that yield ⁇ 30% total hydrolysis of substrate (linear assay conditions).
- the assay is initiated by addition of substrate (1 mM [ 32 P]cGMP), and the mixture is incubated for twelve minutes. Seventy-five (75) ⁇ g of Crotalus atrox venom is then added, and the incubation is continued for three more minutes (fifteen minutes total).
- the reaction is stopped by addition of 200 ⁇ L of activated charcoal (25 mg/ml suspension in 0.1 M NaH 2 PO 4 , pH 4). After centrifugation (750 X g for three minutes) to sediment the charcoal, a sample of the supernatant is taken for radioactivity determination in a scintillation counter and the PDE5 activity is calculated.
- inhibitors of the present invention on enzymatic activity of PDE5 preparations can be assessed in either of two assays which differ from each other principally on the basis of scale and provide essentially the same results in terms of IC 50 values. Both assays involve modification of the procedure of Wells et al., Biochim. Biophys. Ada, 384, 430 (1975). The first of the assays is performed in a total volume of 200 ⁇ l containing 50 mM Tris pH 7.5, 3 mM Mg acetate, 1 mM EGTA, 50 ⁇ g/ml snake venom nucleotidase and 50 nM [ 3 H]-cGMP (Amersham).
- a second, microplate PDE assay uses Multiscreen plates and a vacuum manifold.
- the assay (100 ⁇ l) contains 50 mM Tris pH 7.5, 5 mM Mg acetate, 1 mM EGTA and 250 ⁇ g/ml snake venom nucleotidase.
- the other components of the reaction mixture are as described above.
- the total volume of the assay is loaded on a QAE Sephadex microcolumn plate by filtration. Free radioactivity is eluted with 200 ⁇ l of water from which 50 ⁇ l aliquots are analyzed by scintillation counting as described above.
- a patient who was administered a PDE5 inhibitor of the invention noted an improvement in his Parkinson's symptoms, i.e., a reduction in his symptoms.
- the PDE5 inhibitor was 5-(2-ethoxy-5-(4-methyl- 1 -p ⁇ peraz ⁇ nylsulphonyl)phenyl)-1 -methyl-3-n-propyl-1 ,6-d ⁇ hydro-7H- pyrazolo[4,3-d]pyr ⁇ m ⁇ d ⁇ n-7-one, otherwise known as sildenafil citrate (Viagra®)
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Abstract
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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JP2001576012A JP2004500425A (ja) | 2000-04-19 | 2001-04-17 | パーキンソン病の処置に対する環状gmp特異的ホスホジエステラーゼインヒビターの使用 |
DE60124085T DE60124085D1 (de) | 2000-04-19 | 2001-04-17 | Pde-v hemmer zur behandlung von morbus parkinson |
AU2001255849A AU2001255849B8 (en) | 2000-04-19 | 2001-04-17 | PDE-V inhibitors for treatment of Parkinson's Disease |
AU5584901A AU5584901A (en) | 2000-04-19 | 2001-04-17 | Use of cyclic gmp-specific phosphodiesterase inhibitors for treatment of parkinson's disease |
CA002407031A CA2407031A1 (fr) | 2000-04-19 | 2001-04-17 | Utilisation d'inhibiteurs de phosphodiesterase specifique de gmp cyclique pour le traitement de la maladie de parkinson |
EP01929063A EP1278522B1 (fr) | 2000-04-19 | 2001-04-17 | Utilisation d'inhibiteurs de phosphodiesterase specifique de gmp cyclique pour le traitement de la maladie de parkinson |
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US19818000P | 2000-04-19 | 2000-04-19 | |
US60/198,180 | 2000-04-19 |
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WO2001078711A2 true WO2001078711A2 (fr) | 2001-10-25 |
WO2001078711A3 WO2001078711A3 (fr) | 2002-07-04 |
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EP (1) | EP1278522B1 (fr) |
JP (1) | JP2004500425A (fr) |
CN (1) | CN1436080A (fr) |
AT (1) | ATE343388T1 (fr) |
AU (2) | AU2001255849B8 (fr) |
CA (1) | CA2407031A1 (fr) |
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Cited By (7)
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EP1733728A2 (fr) * | 2001-07-23 | 2006-12-20 | Bayer HealthCare AG | Utilisation d'imidazotriazinones 2-alcoxyphenyl substituées en tant qu'inhibiteurs de la phosphodiestérase |
WO2008144061A2 (fr) * | 2007-05-18 | 2008-11-27 | Vivus, Inc. | Nouvelles compositions comprenant un inhibiteur de phosphodiestérase-5 et leur utilisation dans des procédés de traitement |
US8338420B1 (en) | 2002-12-04 | 2012-12-25 | Mitsubishi Tanabe Pharma Corporation | Treatment of Parkinson's disease and enhancement of dopamine signal using PDE 10 inhibitor |
AU2007217349B2 (en) * | 2006-02-21 | 2013-05-30 | Teva Pharmaceutical Industries, Ltd. | Use of rasagiline for the treatment of Multiple System Atrophy |
US8841300B2 (en) | 2006-10-02 | 2014-09-23 | Jerry M. Held | Treatment for Parkinson's disease—combination high dose serotonergic synaptic reuptake inhibitor with phosphodiesterase inhibitor |
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- 2001-04-17 AT AT01929063T patent/ATE343388T1/de not_active IP Right Cessation
- 2001-04-17 AU AU2001255849A patent/AU2001255849B8/en not_active Ceased
- 2001-04-17 EP EP01929063A patent/EP1278522B1/fr not_active Expired - Lifetime
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Cited By (15)
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EP1733728A3 (fr) * | 2001-07-23 | 2007-03-21 | Bayer HealthCare AG | Utilisation d'imidazotriazinones 2-alcoxyphenyl substituées en tant qu'inhibiteurs de la phosphodiestérase |
EP1733728A2 (fr) * | 2001-07-23 | 2006-12-20 | Bayer HealthCare AG | Utilisation d'imidazotriazinones 2-alcoxyphenyl substituées en tant qu'inhibiteurs de la phosphodiestérase |
US8338420B1 (en) | 2002-12-04 | 2012-12-25 | Mitsubishi Tanabe Pharma Corporation | Treatment of Parkinson's disease and enhancement of dopamine signal using PDE 10 inhibitor |
AU2007217349B9 (en) * | 2006-02-21 | 2013-06-27 | Teva Pharmaceutical Industries, Ltd. | Use of rasagiline for the treatment of Multiple System Atrophy |
EP1991214B1 (fr) * | 2006-02-21 | 2015-08-05 | Teva Pharmaceutical Industries, Ltd. | Utilisation de rasagiline pour traiter une atrophie multisystématisée |
US8809310B2 (en) | 2006-02-21 | 2014-08-19 | Teva Pharmaceutical Industries, Ltd. | Use of rasagiline for the treatment of multiple system atrophy |
AU2007217349B2 (en) * | 2006-02-21 | 2013-05-30 | Teva Pharmaceutical Industries, Ltd. | Use of rasagiline for the treatment of Multiple System Atrophy |
US8841300B2 (en) | 2006-10-02 | 2014-09-23 | Jerry M. Held | Treatment for Parkinson's disease—combination high dose serotonergic synaptic reuptake inhibitor with phosphodiesterase inhibitor |
WO2008144061A3 (fr) * | 2007-05-18 | 2009-02-12 | Vivus Inc | Nouvelles compositions comprenant un inhibiteur de phosphodiestérase-5 et leur utilisation dans des procédés de traitement |
US8440671B2 (en) | 2007-05-18 | 2013-05-14 | Vivus, Inc. | Compositions comprising a phoshodiesterase-5 inhibitor and their use in methods of treatment |
AU2008254424B2 (en) * | 2007-05-18 | 2012-12-20 | Vivus, Inc. | Novel combinations comprising a phosphodiesterase-5 inhibitor and their use |
WO2008144061A2 (fr) * | 2007-05-18 | 2008-11-27 | Vivus, Inc. | Nouvelles compositions comprenant un inhibiteur de phosphodiestérase-5 et leur utilisation dans des procédés de traitement |
US8969417B2 (en) | 2008-06-06 | 2015-03-03 | Pharmatwob Ltd. | Pharmaceutical compositions for treatment of Parkinsons disease |
US9259418B2 (en) | 2008-06-06 | 2016-02-16 | Pharmatwo B Ltd | Pharmaceutical compositions for treatment of Parkinson's disease |
WO2018160067A1 (fr) * | 2017-03-02 | 2018-09-07 | Universiteit Van Amsterdam | Augmentation spécifique de la synthèse de la dopamine par ciblage du récepteur de la guanylate cyclase 2c dans le traitement de la maladie de parkinson |
Also Published As
Publication number | Publication date |
---|---|
US6492371B2 (en) | 2002-12-10 |
CA2407031A1 (fr) | 2001-10-25 |
WO2001078711A3 (fr) | 2002-07-04 |
US20020006926A1 (en) | 2002-01-17 |
JP2004500425A (ja) | 2004-01-08 |
AU2001255849B2 (en) | 2005-12-22 |
AU5584901A (en) | 2001-10-30 |
AU2001255849B8 (en) | 2006-04-27 |
CN1436080A (zh) | 2003-08-13 |
EP1278522B1 (fr) | 2006-10-25 |
US20020077274A1 (en) | 2002-06-20 |
EP1278522A2 (fr) | 2003-01-29 |
DE60124085D1 (de) | 2006-12-07 |
ATE343388T1 (de) | 2006-11-15 |
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